New sequencing technology offers an unprecedented opportunity to systematically survey both common and rare genic variation across well-characterized clinical sample collections, to discover genes conferring susceptibility to disease. The NHLBI has recognized this opportunity and the need to develop these methods into routine and robust production activities. We propose to accomplish this goal by leveraging three areas of expertise of our institute: technology development, large-scale production genome sequencing, and data management and analysis in support of medical genetics. We have developed a novel and efficient approach for targeted sequencing and have already piloted the method at a scale of ~50,000 targets. As one of three NHGRI sequencing centers, we have considerable experience with high-throughput sequencing and currently have the world's largest installed base of next-generation sequencers (including Illumina/Solexa Genome Analyzer, 454 and SOLID machines). As part of multiple NHLBI and NHGRI national genotyping programs, we have created a unique infrastructure highly tailored to Heart, Lung and Blood phenotype and genotype management. During the course of our work we will optimize and validate a cost effective approach for whole exon sequencing, implement our methodology at production scale, and demonstrate production sequencing by generating whole exons sequencing data for hundreds of samples. PUBLIC HEALTH REVELANCE Determining the genetic component of risk of common complex disorders (such as heart disease, diabetes and cancer) can help elucidate underlying biological mechanisms, pinpoint routes for therapy, and offer prediction of disease risk and clinical outcomes. Until recently it has been impossible to undertake, broad, unbiased survey to discover the full spectrum of DNA-based variation in individuals with and without disease, at a scale necessary to uncover statistically significant associations. As such, the aim of this proposal is empower medical genetics by advancing DNA sequencing technology and analysis to a point at which one can routinely sequences all coding parts of the human genome in hundreds to thousands of samples for any given trait.